Motor-evoked potentials in response to fatiguing grip exercise in multiple sclerosis patients.

OBJECTIVE: This study examined central and peripheral effects of fatiguing exercise (3 min maximal grip) in healthy controls (n=10) and multiple sclerosis (MS) subjects with weakness, MS-W (n=16) and normal motor function, MS-NM (n=16) in the studied extremity.Method: Transcranial magnetic stimulation (TMS) was used to assess resting and facilitated motor-evoked potentials (MEPs) of abductor pollicus brevis (APB) and flexor carpi radialis (FCR) muscles before and after fatiguing exercise. Exercise-induced depletion and recovery of phosphocreatine (PCr) were measured using (31)P magnetic resonance spectroscopy ((31)PMRS) in FCR. RESULTS AND CONCLUSION: MS subjects demonstrated significantly lower peak force and a faster decline in force than controls. Contralateral muscle activation (hand grip) before the fatigue protocol resulted in significantly increased MEP amplitudes in all groups. Contralateral hand grip following fatiguing exercise resulted in significantly higher MEP amplitudes in controls and MS-NM subjects, but not MS-W subjects. Fatiguing exercise resulted in prolonged central motor conduction time (CMCT) in MS subjects, but not controls. No group differences in PCr depletion or resynthesis were observed. All groups demonstrated significant post-exercise depression (PED) of MEP amplitude that persisted beyond the time course of PCr recovery, indicating fatigue was central in origin. MS subjects were less able than controls to increase cortical excitability using contralateral muscle activation following fatiguing exercise, possibly indicating impaired conduction in the corpus callosum.     

Computerized hand grip myometry reliably measures myotonia and muscle strength in myotonic dystrophy (DM1)

The aim of this study was to develop a reliable, sensitive, quantitative measure of grip myotonia and strength and to determine whether CTG repeat length is correlated with grip myotonia and with muscle strength in myotonic dystrophy type 1 (DM1). Three maximum voluntary isometric contractions (MVICs) of the finger flexors (i.e., handgrip) were recorded on 2 successive days using a computerized handgrip myometer in 29 genetically confirmed DM1 patients and 17 normals. An automated computer program calculated MVIC peak force (PF) and relaxation times (RTs) along the declining (relaxation) phase of the force recordings at 90%, 75%, 50%, 10%, and 5% of PF. Patients also underwent quantitative strength testing (QST) manual muscle testing (MMT). The patients had longer grip RTs and lower PFs than normals. RT (90% to 5%) was above the normal mean +2.5 SD in 25 (86%) patients. In DM1, prolongation of RT was mainly in the terminal (50% to 5%), rather than the initial (90% to 50%) phase of relaxation. PFs and RTs for each patient were reproducible on consecutive days. RTs were positively correlated with leukocyte CTG repeat length, whereas measures of muscle strength, such as PF, QST, and MMT, were negatively correlated with repeat length. We conclude that computerized handgrip myometry provides a sensitive, reliable measure of myotonia and strength in DM1 and offers a method to assess natural history and response to treatment.     

Muscle fatigue, effects of training and disuse

The study of muscle fatigue started about a century ago, when it was proposed that the observed decrease in force during prolonged voluntary contractions resulted from changes in central processes which reduced the motor drive. In the middle of this century it was noticed that this loss of force could not be restored by maximal electrical stimulation of the motor nerve, and thus the importance of peripheral mechanisms, located beyond the motoneuron, was emphasized. However, it was not clear which peripheral site was most important in decreasing the muscle mechanical capacity during fatigue. More recently, the comparison between peripheral failures during sustained and intermittent contractions indicated that recorded mechanical changes underwent deterioration which was not closely related to the recorded electrical changes. It was thus proposed that muscle intracellular processes dominate the force decrease during muscle fatigue. This concept has been substantiated by the study of standard fatigue tests performed in control, trained, and disused human muscles, as reviewed in this paper.     

Functional relationships of central and peripheral muscle alterations in multiple sclerosis

The functional implications of central motor impairment and peripheral muscle alterations in multiple sclerosis are unclear. Muscle strength, central and peripheral activation, and symptomatic fatigue were investigated in 16 patients with multiple sclerosis (MS) and 18 control subjects. Voluntary and electrically stimulated isometric contractions were obtained from the ankle dorsiflexor muscles. Maximal voluntary contraction (MVC) was 27% lower in MS patients than controls, although electrically stimulated force was similar. Muscle fat-free cross-sectional area (CSA) was similar in both groups. These data indicate central activation impairment in MS. Such impairment in MS was further demonstrated by decreased foot-tap speed, rate of voluntary force development, and central activation ratio. Peripheral activation changes in MS patients were modest. Although stimulated tetanic force was similar, force relaxation was slower in MS patients compared to controls, resulting in a left-shifted force-frequency relationship in MS. Motor function changes were not associated with fatigue but were associated with impaired ambulation. Thus, weakness and walking impairment, but not fatigue, were related to impaired central activation in MS. These findings may help optimize rehabilitation strategies designed to improve function in persons with MS.     

Diminished central activation during maximal voluntary contraction in chronic fatigue syndrome.

OBJECTIVE: We have investigated whether central activation failure (CAF) is increased during local muscle fatigue in chronic fatigue syndrome (CFS). METHODS: Fourteen female CFS patients and 14 age-matched healthy female controls made a 2 min sustained maximal voluntary contraction (MVC) of the biceps brachii muscle. Before, during, and after sustained MVC, electrical endplate stimulation was applied. Force and 5 channel surface EMG (sEMG) were registered. RESULTS: Although force responses upon stimulation during rest did not differ between patients and controls, MVC was significantly lower in patients. Already at the beginning of sustained MVC, CFS patients showed significantly larger CAF than controls (36.5+/-17.0% and 12.9+/-13.3%, respectively). For all individual patients mean CAF over the first 45 s was higher than 30%, while it was below 30% for all controls. Less peripheral fatigue in patients was demonstrated by the changes in muscle fibre conduction velocity and the differences between force responses before and after contraction. CONCLUSIONS: Central activation is diminished in CFS patients. Possible causes include changed perception, impaired concentration, reduced effort and physiologically defined changes, e.g. in the corticospinal excitability or the concentration of neurotransmitters. As a consequence, demands on the muscle are lower, resulting in less peripheral fatigue. SIGNIFICANCE: CFS patients show reduced central activation during MVC. The underlying pathophysiological processes remain still to be determined.     

Long-term electrical stimulation of muscles in children with Duchenne and Becker muscular dystrophy.

Nine children suffering from progressive muscular dystrophy (7 Duchenne and 2 Becker) were included in a program of low-frequency electrical stimulation (LFES) of the right tibialis anterior (TA) muscle. Muscle strength and muscle fatigue were estimated by measuring torques in the ankle during attempts of maximal voluntary contraction (MVC) in the direction of dorsal flexion of the foot and during electrically evoked contractions (EEC). No important increase in the strength of the stimulated muscles was noticed in 4 boys whose muscles were stimulated for 3 months. The muscles of 5 boys who were subjected to electrical stimulation for 9 months showed an improvement; 6 measurements made during the stimulation program revealed that changes of torques in the ankle of the right stimulated extremity were significantly different (P less than 0.001) from the changes of torques in the ankle of the left nonstimulated extremity.     

Changes in characteristics of rat skeletal muscle after experimental allergic encephalomyelitis

Experimental allergic encephalomyelitis (EAE) serves as an animal model for certain neuroinflammatory diseases of the central nervous system, in particular multiple sclerosis (MS). EAE is accompanied by transient weakness or paralysis of hind limbs. We have investigated the effect of partial and transient conduction failure in the central nervous system on skeletal muscle function. At approximately 2.5 days after development of maximal clinical signs, body and medial gastrocnemius muscle mass were lower (by approximately 21 and 33%, respectively; P < 0.05) in EAE rats compared with controls. Fiber cross-sectional area was lower by 40-50% in all fiber types. Maximal force and power were substantially lower (by 58% and 73%) in EAE rats, as was the force normalized for muscle mass (35%). However, no such weakness was found when lower stimulation frequencies were used. Generation of similar submaximal forces was attributable to a slower relaxation in EAE muscles. This advantage for the EAE muscles was lost during repeated exercise. While fatigability was similar, the difference in relaxation rate between EAE and control disappeared in fatigue. Our data suggest that, as a result of central neuroinflammatory diseases, maximal performance of skeletal muscle is impaired but submaximal performance is relatively well maintained.     

Contribution of central and peripheral factors to residual fatigue in Guillain-Barré syndrome

Many patients with Guillain-Barré syndrome (GBS) suffer from severe residual fatigue that has an uncertain basis. We determined the relative contribution of peripheral and central factors during a 2-min fatiguing sustained maximal voluntary contraction (MVC) in 10 neurologically well-recovered GBS patients and 12 age- and sex-matched healthy controls. Physiological fatigue was defined as the decline of voluntary force during an MVC of the biceps brachii. Relative amounts of peripheral fatigue and central activation failure were determined combining voluntary force and force responses to electrical stimulation. Surface electromyography was used to determine muscle-fiber conduction velocity. During the first minute of sustained MVC, peripheral fatigue developed more slowly in patients than in controls. Central fatigue only occurred in patients. The muscle-fiber conduction velocity was higher in patients. The initial MVC, decrease of MVC, initial force response, and initial central activation failure did not significantly differ between the groups. Although peripheral mechanisms cannot be excluded in the pathogenesis of residual fatigue after GBS, these results suggest that central changes are involved. This study thus provides further insight into the factors contributing to residual fatigue in GBS patients.     

Neuromuscular fatigue and aging: central and peripheral factors

A limited number of studies have investigated the effect of old age on neuromuscular fatigue, yet a variety of protocols have been used to compare the fatigability of old and young humans. These include voluntary isometric and isokinetic contraction protocols at maximal and submaximal intensities, and electrical stimulation protocols of continuous or intermittent stimulation at a variety of stimulation frequencies. The results of these studies are summarized in this review. Although it seems reasonable to suggest that age-related changes in muscle morphology and motor unit remodeling, as well as the associated loss of strength and slowed contractile properties, may improve the resistance to neuromuscular fatigue in old humans, the collective results suggest that it is not possible to make this generalization. In fact, it cannot be generalized that the muscles of old humans are either more or less fatigable than young adults because the extent of the difference in fatigability relies strongly on the fatigue task performed (task-dependency). Age-related changes that occur within the neuromuscular system may result in some candidate fatigue sites increasing or decreasing their susceptibility to failure under specific task conditions. These candidate fatigue sites include central drive, muscle membrane excitability, excitation-contraction coupling mechanisms, and metabolic capacities. The effect of old age on these various central and peripheral sites is discussed with respect to their relative contribution during different fatigue tasks. Moreover, the impact of the possible confounding effects of subject habituation, physical activity status, and sex on the fatigability comparison is addressed.     

Fatigue-induced changes in group IV muscle afferent activity: differences between high- and low-frequency electrically induced fatigues

Recordings of group IV afferent activity of tibialis anterior muscle were performed in paralysed rabbits during runs of electrically induced fatigue produced by direct muscle stimulation at a high (100 Hz, high-frequency fatigue HFF) or a low rate (10 Hz, low-frequency fatigue LFF). In addition to analysis of afferent nerve action potentials, muscle force and compound muscle action potentials (M waves) elicited by direct muscle stimulation with single shocks were recorded. Changes in M wave configuration were used as an index of the altered propagation of membrane potentials and the associated efflux of potassium from muscle fibers. The data show that increased group IV afferent activity occurred during LFF as well as HFF trials and developed parallel with force failure. Enhanced afferent activity was significantly higher during LFF (maximal Δf_impulses=249±35%) than HFF (147±45%). No correlation was obtained between the responses of group IV afferents to LFF or to pressure exerted on tibialis anterior muscle. On the other hand, decreased M wave amplitude was minimal with LFF while it was pronounced with HFF. Close correlations were found between fatigue-induced activation of group IV afferents and decreases in force or M wave amplitude, but their strength was significantly higher with LFF compared to HFF. Thus, electrically induced fatigue activates group IV muscle afferents with a prominent effect of low-frequency stimulation. The mechanism of muscle afferent stimulation does not seem to be due to the sole increase in extracellular potassium concentration, but also by the efflux of muscle metabolites, present during fatiguing contractions at low rate of stimulation.     

Abnormal relaxation rates in subjects susceptible to malignant hyperthermia

The acute malignant hyperthermia crisis appears to be mediated by a sudden and sustained rise in the concentration of sarcoplasmic calcium, leading to a prolonged muscle contraction. It is not known whether calcium metabolism in skeletal muscle is abnormal in malignant hyperthermia susceptible (MHS) subjects under normal conditions. A hypermetabolic state in skeletal muscle can be assessed in vivo by measuring relaxation rate. In the present study the relaxation rate was measured in the adductor pollicis muscle after electrical stimulation of the ulnar nerve. Ten MHS subjects with no clinical symptoms of muscle disease were investigated. Relaxation rates were found to be significantly higher in the MH-susceptible subjects compared with controls even under normal conditions (p less than 0.001). Determination of relaxation rate could thus be considered a possible addition to those methods currently available for the diagnosis of MHS.     

Predictive model of muscle fatigue after spinal cord injury in humans

The fatigability of paralyzed muscle limits its ability to deliver physiological loads to paralyzed extremities during repetitive electrical stimulation. The purposes of this study were to determine the reliability of measuring paralyzed muscle fatigue and to develop a model to predict the temporal changes in muscle fatigue that occur after spinal cord injury (SCI). Thirty-four subjects underwent soleus fatigue testing with a modified Burke electrical stimulation fatigue protocol. The between-day reliability of this protocol was high (intraclass correlation, 0.96). We fit the fatigue index (FI) data to a quadratic-linear segmental polynomial model. FI declined rapidly (0.3854 per year) for the first 1.7 years, and more slowly (0.01 per year) thereafter. The rapid decline of FI immediately after SCI implies that a "window of opportunity" exists for the clinician if the goal is to prevent these changes. Understanding the timing of change in muscle endurance properties (and, therefore, load-generating capacity) after SCI may assist clinicians when developing therapeutic interventions to maintain musculoskeletal integrity.     

Myokymia and impaired muscular relaxation with continuous motor unit activity.

We have studied two cases of the syndrome of myokymia and impaired muscular relaxation with continuous motor unit activity. Both patients complained of muscle twitching, weakness, stiffness, and hyperhydrosis during their illness. Myokymia was present over the entire body in both. On repetitive testing of muscle strength each patient showed initial fatigue followed by increasing strength as he continued his efforts. Both patinets improved on phenytoin therapy at high blood levels. Nerve conduction velocities were decreased. Electromyograms showed continuous electrical activity at rest which persisted during sleep and spinal anaesthesia but was diminished by curare. Intravital staining with methylene blue in one case demonstrated sprouting and beading of motor nerve terminals with multiple innervation of muscle fibres. The neurophysiological and pathological findings in these two cases indicate an abnormality of peripheral nerve in this disorder.     

Evidence of an abnormal intramuscular component of fatigue in multiple sclerosis

The goals of this study were to investigate muscle fatigue in patients with multiple sclerosis (MS), and to determine the relationships between muscle fatigue, clinical status, and perceived fatigue. The fatigability of the anterior tibial muscle was quantitated in patients and controls during 9 min of intermittent stimulation (used to eliminate central sources of muscle fatigue). During exercise, the decline in tetanic force, phosphocreatine, and intracellular pH was greater in patients than in controls. The compound muscle action potential amplitude did not decrease during exercise, indicating that there was no failure of neuromuscular transmission during fatigue. Thus, the excessive fatigue in MS developed from sources beyond the muscle membrane. Following exercise, the recovery of tetanic force was delayed in patients (a pattern that suggests abnormal excitation–contraction coupling), whereas the recovery of metabolites was complete in both groups. Muscular fatigue was correlated with clinical disability but not with perceived fatigue. These results suggests that fatigue in MS has both central (perception, upper motor neuron dysfunction) and peripheral (impaired metabolism and excitation–contraction coupling) components.© 1995 John Wiley &Sons, Inc.     

Experienced and physiological fatigue in neuromuscular disorders

ObjectiveFatigue has been described as a typical symptom of neurological diseases. It might be caused both by changes at the peripheral and at the central level. This study measured the level of experienced fatigue and physiological correlates of fatigue in three genetically defined neuromuscular disorders.MethodsSixty-five facioscapulohumeral dystrophy (FSHD), 79 classical myotonic dystrophy (DM), 73 hereditary motor and sensory neuropathy type I (HMSN) patients and 24 age-matched healthy controls made a 2-min sustained maximal voluntary contraction of the biceps brachii muscle. Experienced fatigue at the current moment was assessed with the abbreviated fatigue questionnaire just before the physiological measurement. Peripheral fatigue was quantified by comparing the amplitudes of an initial and a final stimulated force response during rest. Muscle fibre conduction velocity was determined from a 5-channel surface EMG recording in order to show peripheral changes during the contraction. Central aspects of fatigue were measured using superimposed electrical endplate stimulation.ResultsPatients showed an increased level of experienced fatigue. Total physiological and peripheral fatigue were smaller in patients compared to controls, and central fatigue was normal. The most interesting result of this study was the presence of a large central activation failure (CAF) in all groups of neuromuscular patients; they showed CAF values of 36–41% already directly at the start of sustained contraction, whereas the control group showed only 12%. CAF slightly correlated with the level of experienced fatigue just before the test.ConclusionsThe cause of the large CAF in patients is unclear. Reduced concentration, motivation or effort can lead to lower central activation. In neuromuscular patients especially fear of physical activity or fear to damage the muscle or nerve tissue may contribute. Besides, also physiological feedback mechanisms or changes at the motocortical level may be a cause of reduced central activation.SignificanceFor the clinician it is important to know that experienced fatigue is part of the clinical spectrum of neuromuscular patients. Besides, the weakness in these patients is aggravated by reduced central activation. Potentially, both problems could be subject of an intervention.     

Exercise performance and fatiguability in patients with chronic fatigue syndrome.

To examine the role of delay in recovery of peripheral muscle function following exercise in the fatigue experienced by patients with the chronic fatigue syndrome (CFS) and to examine the influence of effort perception in limiting exercise performance in these patients, a study was carried out on a group of twelve patients with chronic fatigue syndrome and 12 sex and age-matched sedentary control subjects. Symptom limited incremental cycle exercise tests including measurements of perceived exertion were performed followed by examination of the contractile properties of the quadriceps muscle group for up to 48 hours. Muscle function was assessed by percutaneous electrical stimulation and maximum voluntary contractions. Muscle function at rest and during recovery was normal in CFS patients as assessed by maximum isometric voluntary contraction, 20:50 Hz tetanic force ratio and maximum relaxation rate. Exercise duration and the relationship between heart rate and work rate during exercise were similar in both groups. CFS patients had higher perceived exertion scores in relation to heart rate during exercise representing a reduced effort sensation threshold of 3.2 units on an unmodified Borg scale in CFS patients. Patients with chronic fatigue syndrome show normal muscle physiology before and after exercise. Raised perceived exertion scores during exercise suggest that central factors are limiting exercise capacity in these patients.     

Muscle function in patients with primary hyperparathyroidism

The muscle contraction of the anterior tibial muscle was investigated by measurements of electrically stimulated and computer-analyzed muscle twitches in 18 unselected patients with primary hyperparathyroidism (HPT) and in 20 healthy control persons. The HPT patients had a lower muscle twitch tension (TT) at single stimulation, compared with the control group [76 +/- 24 N (SD) and 99 +/- 33 N respectively, P less than 0.05]. At high-frequency stimulation the difference in muscle force increased, and at 20 Hz stimulation the force in the HPT patients was 73% of that in the controls (P less than 0.01). There were no differences between the HPT patients and the control persons in neither contraction time nor half relaxation time at single muscle twitch nor in twitch potentiation after 20 and 90 seconds maximal voluntary contraction. The results indicate that patients with primary HPT have an impaired muscle function of probable importance for their symptoms of weakness and generalized fatigue.     

Central fatigue assessed by transcranial magnetic stimulation

Central fatigue is a subjective phenomenon which can be examined using transcranial magnetic stimulation (TMS). To assess central fatigue, we compared TMS and peripheral electrical stimulations in patients with central nervous system (CNS) lesions and controls before and after an exhaustive task. The recovery times of motor evoked potential (MEP) amplitudes were significantly prolonged in the patient group whereas the recovery of F waves and compound muscle action potentials showed no significant changes. The results indicate that fatigue cannot be attributed either to intramuscular processes or to reduced spinal excitability, but reflects a supraspinal, probably cortical phenomenon. The measurement of MEP recovery times proved to be a simple and objective tool for the assessment of fatigue and for the differentiation between healthy controls and patients with CNS lesions. © 1996 John Wiley & Sons, Inc.     

Long‐lasting in vivo inotropic effects of the K+ channel blocker 3,4‐diaminopyridine during fatigue‐inducing stimulation

Blocking K⁺ channels with aminopyridines enhances muscle contractile performance in vitro, but the improvements are relatively short‐lasting during fatigue‐inducing stimulation. We hypothesized that in vivo inotropic actions persist over long periods of fatigue‐inducing stimulation. The effects of 3,4‐diaminopyridine (DAP) were evaluated for rat extensor digitorum longus (EDL) muscle. DAP increased twitch force by 105%. There was a significant leftward shift in the force–frequency relationship, with force values being increased at frequencies up to and including 20 HZ . During repetitive fatigue‐inducing 20‐HZ stimulation, DAP‐induced force increases were large and persisted significantly for at least 30 minutes. Thus, DAP substantially improves contractile performance of EDL muscle in vivo for much longer periods during fatigue‐inducing contractions than in vitro. These data provide support for a potential role for aminopyridines as inotropic agents in applications such as functional electrical stimulation, in which low to medium stimulation frequencies are typically utilized. Muscle Nerve 38: 1616–1622, 2008     

Nonvolitional assessment of muscle endurance in idiopathic inflammatory myopathies: There is no relationship between patient‐reported fatigue and muscle fatigability

Introduction: We investigated whether muscle endurance differs between IIM patients and controls and if a relationship exists between perceived fatigue and poor muscle endurance. Methods: Quadriceps contractility, measured using femoral nerve stimulation (TwQ), and strength, measured using maximal voluntary contraction (MVCQ), were assessed in 20 IIM patients and matched controls. Quadriceps endurance was assessed using repetitive electrical stimulation (3 minutes). Time for force to fall to 70% initial force was determined (T70). Reported fatigue was measured using the FACIT‐F/Fatigue Severity Scales. Results: TwQ and MVCQ were lower and perceived fatigue greater for patients. There was no difference in T70 between groups. No relationships were observed between perceived fatigue and endurance (T70). Conclusions: IIM patients reported more fatigue and were weaker than controls, but there was no difference in muscle endurance. Endurance and strength were unrelated to reported fatigue measures. Mechanisms driving perceived IIM fatigue are likely to be multifactorial. Muscle Nerve 50 : 401–406, 2014